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Compound as well as preparation method and application thereof

A compound and catalyst technology, applied in the field of bile acid conjugated pyrrole amide glycogen phosphorylase inhibitors, can solve the problems of difficult dissociation and direct connection of chemical bonds, and achieve good GP inhibitory activity and the effect of maintaining activity

Active Publication Date: 2015-06-10
SOUTH CHINA UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Because most targeting carriers and small molecule drugs cannot be directly connected by chemical bonds, or the chemical bonds formed by the direct connection of the two are difficult to dissociate further, releasing small molecule drugs

Method used

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  • Compound as well as preparation method and application thereof
  • Compound as well as preparation method and application thereof
  • Compound as well as preparation method and application thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Compound I 1 Preparation

[0041]

[0042] 3α-Methanesulfonyloxy-7α,12α-Dihydroxy-5β-cholestane-24-carboxylic acid methyl ester(III)

[0043] Under ice bath, dissolve methyl cholate (0.19g, 0.66mol) in pyridine (10mL), add p-toluenesulfonyl chloride (97mg, 0.79mmol) and DMAP (97mg, 0.79mmol) with stirring, and stir overnight at room temperature. The next day, it was concentrated under reduced pressure, the residue was diluted with ethyl acetate, washed with saturated brine, and anhydrous Na 2 SO 4 Dry, evaporate the solvent under reduced pressure, flash column chromatography (petroleum ether / ethyl acetate 1 / 1, V / V) to obtain a white solid (1.09 g, 95%). ESI-MS:500.5[M+H] + ; 1 H NMR(400MHz, CDCl 3 )δ: 0.66 (s, 3H), 0.87 (s, 3H), 0.94 (d, J = 6.3 Hz, 3H), 2.38-1.25 (m, 25H), 2.56-2.52 (m, 1H), 2.48 (s ,3H), 3.68(s,3H), 3.84(s,1H), 7.32(d,J=8.0Hz,2H), 7.79(d,J=8.4Hz,2H).

[0044] 3α-hydroxyethoxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylic acid methyl ester (V 1 )

[0045] 3α-...

Embodiment 2

[0051] Compound I 2 Preparation

[0052]

[0053] 3α-(Hydroxyethoxy)ethoxy-7α,12α-Dihydroxy-5β-cholestane-24-carboxylic acid methyl ester (V 2 )

[0054] Refer to the preparation method of 3α-hydroxyethoxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylic acid methyl ester to obtain a white solid (174 mg, 41%). ESI-MS:511.4[M+H] + ; 1 H NMR(400MHz, CDCl 3 )δ:0.62(s,3H),0.85(s,3H),0.91(d,J=6.4Hz,3H),1.97-1.03(m,21H),2.18-2.03(m,5H),3.47-3.45 (m, 2H), 3.65-3.54 (m, 10H).

[0055] 3α-(sulfonyloxyethoxy)ethoxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylic acid methyl ester (VI 2 )

[0056] Refer to the preparation method of 3α-methanesulfonyloxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylate to obtain a white solid (159mg, 51%). ESI-MS: 682.5[M+18] + ; 1 H NMR(400MHz, CDCl 3 )δ:0.62(s,3H),0.84(s,3H),0.91(d,J=6.0Hz,3H),1.96-1.05(m,22H),2.35-2.03(m,4H),2.37(s ,3H),3.65-3.36(m,10H),3.79(s,1H),7.27(d,J=8.0Hz,2H),7.74(d,J=8.0Hz,2H).

[0057] (3α-Oxyethoxyethoxy-cholic acid-yl)-{1-[2-(5-chloro-1H-py...

Embodiment 3

[0060] Compound I 3 Preparation

[0061]

[0062] 3α-[(hydroxyethoxy)ethoxy]ethoxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylic acid methyl ester (V 3 )

[0063] Refer to the preparation method of 3α-hydroxyethoxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylate to obtain a white solid (516 mg, 24%). ESI-MS: 555.5[M+H] + ; 1 H NMR(400MHz, CDCl 3 )δ: 0.62 (s, 3H), 0.84 (s, 3H), 0.91 (d, J = 5.6 Hz, 3H), 1.98-1.01 (m, 21H), 2.30-2.02 (m, 5H), 2.90-2.65 (s,1H),3.66-3.44(m,16H).

[0064] 3α-[(sulfonyloxyethoxy)ethoxy]ethoxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylic acid methyl ester (VI 3 )

[0065] Refer to the preparation method of 3α-methanesulfonyloxy-7α,12α-dihydroxy-5β-cholestane-24-carboxylate to obtain a white solid (870mg, 27%). ESI-MS:726.5[M+18] + ; 1 H NMR(400MHz, CDCl 3 )δ:0.62(s,3H),0.83(s,3H),0.91(d,J=6.0Hz,3H),1.95-1.05(m,22H),2.35-2.03(m,4H),2.38(s ,3H),3.50(s,1H),3.64-3.41(m,14H),3.78(s,1H),7.27(d,J=8.4Hz,2H),7.73(d,J=8.4Hz,2H) .

[0066] (3α-Oxyethoxyethoxyethoxy-cho...

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Abstract

The invention discloses a compound having a structure formula I as shown in the specification, a preparation method and application thereof as well as pharmaceutically acceptable salts or esters of the compound. The compound is a novel cholic acid conjugated pyrrole amide based glycogen phosphorylase inhibitor, can take effect on glycogen phosphorylase of the liver effectively and can function as an optimal medicine for patients with type II diabetes to control blood sugar. The compound can be used for preparing medicines for resisting diabetes and complication thereof, medicines for resisting cardiovascular diseases, medicine for reducing weight and medicines for treating metabolic syndromes.

Description

Technical field [0001] The invention relates to the field of medicinal chemistry, in particular to a new type of cholic acid conjugated pyrrolamide glycogen phosphorylase inhibitor. It also relates to their preparation methods and pharmaceutical compositions containing them. Such compounds can be used to prepare anti-diabetic and its complications drugs, anti-cardiovascular disease drugs, weight-loss drugs, and drugs for treating metabolic syndrome. Background technique [0002] At present, there are more than 92 million diabetic patients in my country, making China the world's largest diabetes country, and about 97% of them are type 2 diabetes. At present, the treatment of type 2 diabetes is divided into insulin and its similar drugs, insulin sensitizers, insulin secretagogues, carbohydrate reducing regulators, etc., according to the different pharmacological action mechanisms of drugs. But these drugs have limited hypoglycemic effect. With the deepening of people's understan...

Claims

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Application Information

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IPC IPC(8): C07J43/00A61K31/58A61P3/10A61P3/04A61P3/06A61P9/10A61P9/12A61P3/00
CPCC07J43/003
Inventor 李晶张丽颖张雷吴芳萍
Owner SOUTH CHINA UNIV OF TECH
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